Abstract
AIM: One of the main therapeutic approaches to prevent symptoms and slow the progression of Alzheimer's disease (AD) is cholinesterase inhibitors. For this purpose, some novel 2-pyrazoline-1-carboxamide derivatives based on cuminaldehyde were synthesized. MATERIALS AND METHODS: IR, (1)H-NMR, (13)C-NMR and elemental analysis were used to confirm the structures of the synthesized compounds. The antioxidant and cholinesterase (ChE) activities of the compounds were evaluated. Molecular docking and molecular dynamics (MD) simulations were performed to investigate the interaction of the reference and the lead compound at the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) proteins. Molecular Electrostatic Potential (MEP) and Frontier Molecular Orbitals (FMO) for the synthesized compounds were calculated using DFT calculations. RESULTS AND CONCLUSION: Compounds 7 and 8 exhibited the best antioxidant activity. Compounds 7 and 8 were also the most potent compounds against AChE and BChE with IC(50) values of 2.77-3.09 µM and 6.16-6.79 µM, respectively, compared to galantamine (IC(50) = 1.90 µM for AChE and IC(50) = 46.51 µM for BChE). In silico studies showed that compound 7 binds to both targets with higher affinity than the reference compound, galantamine. ADME studies also showed that compound 7 can cross the blood-brain barrier.